A multi-disciplinary approach to understand the mechanisms of immunotoxicity induced by the dual-antibiotic combination of vancomycin and tazocin

Description

Vancomycin is a complex glycopeptide antibiotic that is widely used for the treatment of drug-resistant bacterial infections. The use of vancomycin is associated with serious adverse reactions such as drug rash with eosinophilia with systemic symptoms (DRESS), which is associated with the expression of human leukocytes antigen (HLA) HLA-A*32:01, suggesting that immune-mediated mechanisms may contribute to this adverse event. More importantly, when combined with beta-lactam antibiotics as first-line therapy for severe infections in intensive care units, concomitant vancomycin with tazocin (piperacillin-tazobactam, VPT) has been associated with greater incidence of acute kidney injury (AKI) than that with vancomycin monotherapy or that with vancomycin and other beta-lactam antibiotics combination therapy. The pathogenesis of this AKI remains uncertain but may be a synergistic phenomenon since tazocin alone is rarely associated with AKI. The infiltration of mononuclear cells in kidney biopsy and co-presentation of DRESS in patients with VPT induced AKI suggest the involvement of immune-mediated mechanisms. 

Our preliminary studies have shown that (i) lymphocytes from patients with cutaneous adverse events can be activated with vancomycin or tazocin and (ii) vancomycin can form covalent adducts with tazocin. However, how the combination of vancomycin and tazocin activate immune cells remains to be defined. This project aims to combine therapeutic drug monitoring and characterisation of T-cell responses to VPT so that individuals with high risk of AKI can be prescribed with optimal drug regimens including choice of concurrent antibiotics, dosing, and duration of therapy. The outcome of the project will be non-invasive screening assays that will enable early diagnosis of AKI and rapid discontinuation (or dose reduction) of the offending reagents for kidney function recovery. These assays will have significant clinical impact by translating laboratory findings into patient care.

This project is a collaboration between active research groups in Liverpool and Newcastle. The project includes three objectives: (1) therapeutic drug monitoring. It has been hypothesized that tazocin may synergistically augment vancomycin toxicity through the cast formation by intratubular vancomycin crystallization. Thus, mass spectrometry will be used to quantify vancomycin, piperacillin and vancomycin-piperacillin conjugate levels in plasma and urine; (2) characterisation of drug-specific memory T-cell responses in patients with AKI. The presence of vancomycin-, piperacillin- and vancomycin-piperacillin conjugate-specific T cells will be characterised. T-cell clones will be generated and assessed for cellular phenotype and function, drug cross-reactivity and HLA allele restriction of the T-cell response; (3) volunteer studies to assess the origin of drug-specific T-cells. The in vitro priming of naïve T-cells with culprit drugs will be assessed using an HLA genotyped cell bank containing PBMCs from 1000 healthy donors. Drug-responsive T-cell clones will be generated and compared to patient cells.

You will be based at the Centre for Drug Safety Science at the University of Liverpool under the supervision of Dr Xiaoli Meng, a senior bioanalytical specialist who has expertise in defining drug-associated antigens using mass spectrometry, and Prof Dean Naisbitt, who holds the Chair of Drug Safety Science in the University of Liverpool and is head of immunopharmacology. There will be opportunities to spend time at Newcastle University and you will be supervised by Prof Gareth Veal at Newcastle university, who has expertise in therapeutic drug monitoring and is actively involved in running early phase and clinical pharmacology trials supported by Cancer Research UK. The supervisors and their group members will provide you with training in clinical medicine, cellular immunology, mass spectrometry and drug safety science.

The successful applicant should have an interest in drug hypersensitivity, immunology and disease biomarkers.  Applicants should have (or be expected to obtain) at least an upper second class (2:1) degree in a Biological or Life Science subject.